tbuckley/cabot-search huggingface dataset:
CAPItello-280: A phase III study of capivasertib and docetaxel versus placebo and docetaxel in metastatic castration-resistant prostate cancer.
Authors: Simon J. Crabb, Ding-Wei Ye, Hirotsugu Uemura, Thomas Morris, Christopher Gresty, Jill Logan, Claire Rooney, Andrew Foxley, Michael Anthony Carducci
Journal: Journal of Clinical Oncology (2023)

TPS287 Background: Docetaxel is the standard first-line chemotherapy for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed on an androgen receptor-targeted agent (ARTA; typically, abiraterone, enzalutamide, apalutamide, or darolutamide). However, most patients develop chemotherapy resistance, and median overall survival (OS) remains under 3 years. Preclinical studies have associated phosphoinositide 3-kinase (PI3K)/protein kinase (AKT)/phosphatase and tensin homolog (PTEN) pathway signaling with the development of mCRPC and with resistance to taxane chemotherapy. The ProCAID Phase II trial (NCT02121639) examined whether adding capivasertib, a potent, selective inhibitor of all three AKT isoforms (AKT1/2/3), to docetaxel chemotherapy improved clinical outcomes. Although no difference in the primary endpoint (composite progression-free survival [PFS]) was detected, OS, a secondary endpoint, was extended in the capivasertib plus docetaxel treatment group. A subsequent follow-up analysis at advanced maturity suggested that the OS benefit in ProCAID was restricted to patients who had received prior treatment with an ARTA. Methods: CAPItello-280 is a Phase III study to confirm the efficacy and safety of capivasertib in combination with docetaxel compared with placebo and docetaxel in patients with mCRPC who have not previously received chemotherapy for mCRPC, but whose disease has progressed despite treatment with an ARTA in any setting. Approximately 790 patients will be randomized 1:1 to receive either capivasertib or matching placebo (320 mg orally, twice daily [BD], 4 days on, 3 days off) plus docetaxel (75 mg/m 2 on day 1 of each 21-day cycle for 6–10 cycles, with prednisone or prednisolone 5 mg BD or 10 mg once daily) with a background of continued androgen deprivation therapy until disease progression, unacceptable toxicity, death, or withdrawal of consent. The primary endpoint is OS; secondary endpoints include radiographic PFS, time to pain progression, symptomatic skeletal events, safety, and tolerability. Recruitment began in March 2022 and is planned at 207 study sites in 20 countries, including the USA, Canada, Europe, South America, and Asia-Pacific. Clinical trial information: NCT05348577 .
Predictive biomarkers for the oncolytic virus, JX-594, through the HIF-dependent interferon beta pathway in metastatic renal cell carcinoma.
Authors: Jee Soo Park, Myung Eun Lee, Won Sik Jang, Jongchan Kim, Namhee Lee, Keunhee Oh, Won Sik Ham
Journal: Journal of Clinical Oncology (2023)

710 Background: Although combination approaches with an immunotherapy are established as the first-line setting in metastatic renal cell carcinoma (mRCC), immunotherapy are only efficacious for a subset of patients. Our group has been working on improving the benefit of immunotherapy using JX-594 (pexastimogene devacirepvec, Pexa-vec) in mRCC. The purpose of this study is to develop predictive biomarker for JX-594 in metastatic clear cell RCC (ccRCC). Methods: Using ccRCC cell lines representative of each four mutations (786-O (VHL mutation), Caki-2 (VHL and PBRM1 mutation), A-498 (VHL and SETD2 mutation), and 769-P (VHL and BAP1 mutation)), four cell line-derived xenograft (CDX) mouse models have been developed. 2-10x10 6 tumor cells were subcutaneously injected into the right flank of wild-type BALB/c nude mice. When tumors reached &gt;50 mm 3 , mice were treated with either PBS or 1x10 7 plaque-forming units of JX-594 by intratumoral injection in day 0, 3, and 6. Interferon beta (IFN-β) expression were measured with qRT-PCR after the JX-594 treatment in 786-O CDX model. Results: All CDX models demonstrated significant decrease in tumor size by the JX-594 compared to control. Most rapid tumor growth was observed in BAP1-deficient xenografts while PBRM1-deficient xenografts demonstrated the slowest growth among four xenografts. The decrease of tumor volume by the JX-594 was most pronounced in BAP1-deficient tumors compared to VHL, PBRM1, and SETD2 mutation tumors. Even after adjusting the relative differences of tumor growth rate in each model, xenografts with BAP1 loss were still associated with significantly better response to JX-594. IFN-β expression significantly decreased in BAP1-deficient tumors compared to other tumors, while the expression level was recovered dramatically after JX-594. Conclusions: BAP1-deficient tumors demonstrated rapid tumor progression while they were most significantly reduced after JX-594. BAP1-deificient tumors had decreased levels of IFN-β expression while it was most dramatically recovered after JX-594, suggesting the mechanism of JX-594 through the HIF-dependent interferon beta induction. This is the first study to elucidate the potential of BAP1 as predictive biomarker for JX-594 and its underlying mechanisms.
Prognostic value of pretreatment lung immune prognostic index in patients with metastatic hormone-sensitive and castration-resistant prostate cancer.
Authors: Zhipeng Wang, Haoyang Liu, Jinge Zhao, Pengfei Shen, Hao Zeng
Journal: Journal of Clinical Oncology (2023)

198 Background: The aim of this study was to explore the prognostic value of the lung immune prognostic index (LIPI) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Methods: We retrospectively analyzed data of 502 mHSPC patients primarily treated with maximal androgen blockade and 158 mCRPC patients receiving abiraterone. All cases were classified into the LIPI-Good, LIPI-Intermediate, and LIPI-Poor groups based on their LIPI score calculated by the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase. The potential of LIPI in predicting mCRPC-free survival (CFS), PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) were analyzed. A propensity score matching (PSM) methodology was performed to balance the baseline factors of different groups. Results: In the mHSPC cohort, patients of the LIPI-Good (mCFS: 25.7 mo; mOS: 93.3 mo), LIPI-Intermediate (mCFS: 14.8 mo; mOS: 51.9 mo) and LIPI-Poor group (mCFS: 6.8 mo; mOS: 18.5 mo) had sequentially worse clinical outcomes (P&lt;0.001 for all pairwise comparisons). The results remain consistent after PSM. Multivariate Cox regression further confirmed that LIPI was an independent predictor of survival outcomes. Subgroup analysis verified that LIPI was associated with unfavorable prognosis in all subgroups except for cases with visceral metastases or receiving abiraterone/docetaxel. As for patients with CRPC receiving abiraterone, LIPI was also an indicator of poor prognosis. Specifically, cases in the LIPI-Good, LIPI-Intermediate and LIPI-Poor group had a ladder-shaped worse PSA response (71.4% [50/70] vs. 56.5% [39/69] vs. 36.8% [7/12], P=0.015), PSA-PFS (14.9- vs. 9.3 vs. 3.1 mo, P&lt;0.001) and OS (14.6- vs. 32.3- vs. 53.4 mo, P&lt;0.001). The results were robust even after PSM. Multivariate Cox regression confirmed that LIPI was an independent prognosticator of abiraterone. Conclusions: This study demonstrated that baseline LIPI was a significant prognostic biomarker for both mHSPC and mCRPC patients and could potentially facilitate risk classification and treatment-decision making in clinical practice.
Impact of neoadjuvant chemotherapy on pathological stage and survival in sarcomatoid bladder cancer.
Authors: Arya Mariam Roy, Karan Jatwani, Vasanthan Muthusamy Kumarasamy, Stuthi Perimbeti, Changchuan Jiang, Kush Gupta, Khurshid Guru, Gurkamal S. Chatta, Dharmesh Gopalakrishnan
Journal: Journal of Clinical Oncology (2023)

530 Background: Sarcomatoid bladder cancer is an extremely rare and aggressive histological variant with poor prognosis and limited consensus regarding its management given rarity and lack of high-quality data. Radical cystectomy (RC) is the mainstay of treatment in muscle-invasive disease and adjuvant therapy is often offered to eligible patients with high-risk features. Data regarding the role of neoadjuvant chemotherapy (NAC) for this variant is limited. Methods: The National Cancer Database was queried to identify patients diagnosed with sarcomatoid bladder cancer from 2004 to 2018. Patients older than 18 years with cT2-4aN0-1M0 sarcomatoid bladder cancer who received curative-intent surgery were included in the analyses. Clinical T4b/N2-3/M1 disease and receipt of adjuvant chemotherapy were employed as exclusion criteria. The population was divided into two cohorts based on the receipt of NAC. Chi-Square and Mann Whitney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed to adjust for confounding factors associated with overall survival. Models were adjusted for age, race, sex, income, stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 573 patients were identified - 70% were males and 93% were White; 139 (25%) received NAC (NAC + ) while 434 (75%) did not (NAC - ). NAC + patients were younger (65 vs 71 years, p &lt; 0.001). Downstaging to pT0-1N0 at the time of RC was significantly more frequent in the NAC + group compared to the NAC - group (32 (24.5%) vs. 28 (6.8%), p = 0.001). Overall survival (OS) was also significantly longer in the NAC + group (median of 40.8 vs. 19.4 months, log-rank p = 0.003). On multivariable analysis, NAC + (Hazard Ratio (HR) = 0.73, 95% CI 0.56-0.91, p = 0.02), pathological downstaging to pT0-1N0 (HR = 0.5, 95% CI 0.31- 0.8, p &lt; 0.001), and any pathological upstaging (HR 4.1, 95% CI 1.5-6.6, p &lt; 0.001) were independently associated with all-cause mortality, while other factors were not (Table). Conclusions: In this large retrospective analysis, administration of NAC in muscle-invasive sarcomatoid bladder cancer was associated with higher rates of downstaging to non-muscle-invasive disease at the time of RC and reduced all-cause mortality. [Table: see text]
Evaluation of the aggressive variant prostate cancer molecular profile (AVPCm) in CLIA environments.
Authors: Paul Vincent Viscuse, Miao Zhang, Prih Rohra, Rebecca Slack Tidwell, Colin C. Pritchard, Sumit Kumar Subudhi, Patrick Glen Pilié, Christopher Logothetis, Paul Gettys Corn, Ana Aparicio
Journal: Journal of Clinical Oncology (2023)

250 Background: 20-30% of prostate cancers respond poorly to androgen receptor (AR)-directed therapies and have an atypical, virulent course. The aggressive variant prostate cancers ( AVPC) encompass virulent androgen indifferent tumors and are characterized by combined defects in ≥ 2/3 of TP53, RB1, and PTEN (AVPC-m). Post-hoc analysis in a phase I/II trial indicated a benefit of carboplatin+cabazitaxel in men with AVPCm + metastatic castrate resistant prostate cancer (mCRPC). We assess the feasibility of detecting the AVPCm in CLIA-certified environments. Methods: Men with progression of mCRPC undergoing biopsies for standard molecular profiling at MD Anderson Cancer Center (MDACC) were eligible. TP53, RB1, and PTEN expression was assessed by immunohistochemistry (IHC) and read by 2 pathologists independently. Next generation sequencing of solid tumor DNA (stDNA) and circulating tumor DNA (ctDNA) was performed on the MDACC Molecular Diagnostics Laboratory and the University of Washington OncoPlex ctDNA platforms respectively . Results: Of 64 eligible patients, 49 (77%), 37 (58%), and 54 (84%) had results reported for IHC, stDNA, and ctDNA respectively. Concordance of IHC reads between pathologists was variable: Kappa 0.78, 0.67, and 0.91 for TP53, RB1, and PTEN respectively. 36 (66.7%) ctDNA samples had low tumor content, such that false negatives could not be excluded. AVPC-m was detected in 14 (29%) of patients by IHC per the original reading pathologist, 2 (5%) by stDNA NGS, and 7 (39%) by ctDNA NGS. Median turnaround times for IHC, stDNA and ctDNA were 12 (2-35), 28 (12-56) and 16 (11-56) days respectively. Conclusions: We show the operational characteristics of the AVPCm detection using CLIA certified assays. IHC detected a greater proportion of patients with AVPCm + tumors than stDNA, likely due, partly, to the challenges of copy number loss detection. ctDNA detected the greatest proportion of AVPCm + tumors but was not evaluable in two thirds of patients. These data serve to inform the design of clinical trials using AVPCm as a criterion for patient selection or stratification. [Table: see text]
Association of primary tumor radiomic phenotypes and outcomes in patients (pts) with metastatic renal cell clear cell carcinoma (mRCC) treated with cytoreductive nephrectomy (CN).
Authors: Mateus Trinconi Cunha, Lucas Stangler, Pedro Freire, Paulo Victor Alves Pinto, Fernando Morbeck Almeida Coelho, Públio Viana, Mauricio Cordeiro, William Carlos Nahas, Jose Mauricio Mota
Journal: Journal of Clinical Oncology (2023)

622 Background: Despite the advances in systemic therapy for mRCC, CN may benefit a subset of pts. We investigated the correlation of clinical outcomes with primary tumor radiomics and radiology measurements of primary and metastatic lesions in mRCC pts treated with CN. Methods: We searched our institutional database for mRCC pts referred for CN from July 2011 to October 2019. Key eligibility criteria included clear cell histology, measurable metastatic disease, and OS &gt;60 days from CN, to avoid surgery-related deaths. Demographics and IMDC risk strata were collected from medical charts. Volumetry and radiomic features (first and second order) were assessed in the arterial phase abdominal computerized tomography (CT) of the primary lesion. Metastatic disease foci were segmented from venous phase CT and measured. Bone disease and &lt;1cm visceral metastases were disregarded for 3-axial measurement. After dimensionality reduction of the radiomic features with Uniform Manifold Approximation and Projection, an unsupervised Gaussian Mixture Model (GMM) clustering was performed. Characteristics of different clusters were compared with Mann-Whitney U test and univariate Cox regression estimated the effect on outcomes. Results: From 54 mRCC pts treated with CN, 39 were included. Median age was 60 years-old. Most patients were male (74%) and intermediate-risk by IMDC (64%). Sites of metastasis included lung (44%), bone (38%), and adrenal (21%). GMM identified 4 distinct clusters from radiomic features, which were grouped according to median OS relative to all pts (2.8 years): Group A (below mOS) and Group B (above mOS). The table shows the association of different factors with OS. Group B had longer median OS (3.4 vs. 1.8 years, p=0.009), progression-free survival (16.8 vs. 9.8 months, p=0.024), systemic treatment-free survival (9.5 vs. 3.8 months, p=0.028), and survival during first-line tyrosine kinase inhibitor (2.2 vs. 0.9 years, p=0.016). Group men had a lower primary-to-whole-body burden ratio compared to Group A (median 0.83 vs. 0.99, p&lt;0.01). Only IMDC risk criteria (HR 1.97, p&lt;0.01) and radiomic group B (HR 0.35, p=0.01) correlated with OS in univariate Cox analysis. Conclusions: Our study suggests that radiomics of the primary lesion may predict OS in mRCC pts after CN, despite limited by its retrospective nature and small sample size. Further validation in larger datasets is warranted. Univariate Cox proportional hazards of prognostic factors on OS. [Table: see text]
Study of cabozantinib in second line under real-life setting in patients with advanced renal cell carcinoma (aRCC): Study design of a French retrospective, multicenter study (OCTOPUS).
Authors: Antoine Thiery-Vuillemin, Loic Mourey, David Pasquier, Constance Thibault, Jean-Christophe Bernhard, Laetitia Zara, Valérie Perrot, Laurence Albiges
Journal: Journal of Clinical Oncology (2023)

TPS744 Background: Cabozantinib is a tyrosine kinase inhibitor (TKI) directed against VEGFR, MET and AXL. In the pivotal phase III METEOR study, cabozantinib demonstrated significantly improved progression-free survival (PFS), overall response rate (ORR) and overall survival (OS) versus everolimus in patients with previously treated aRCC with clear-cell component. Thus, cabozantinib received marketing authorization from the European Medicine Agency in September 2016 for the treatment of aRCC in patients previously treated with a VEGF-targeted therapy. Cabozantinib effectiveness and safety have been investigated in several real-world evidence studies such as CABOREAL or CASSIOPE. However, many questions arising during the routine care of patients with aRCC treated by cabozantinib remain unanswered by the current literature. Therefore, the aims of OCTOPUS study are to describe the effectiveness and safety of 2 nd line cabozantinib in a real-life setting in France and to address these unanswered questions in certain patients subgroups. Methods: Octopus is a multicenter (25 centers), retrospective, non-comparative, non-interventional study in patients with aRCC initiating cabozantinib in 2 nd line in France. The primary endpoint is the duration of treatment (DOT) with cabozantinib: median DOT will be estimated using Kaplan Meier method. Key secondary endpoints to be assessed are: best overall response (BOR), PFS, adverse events (AEs) and subsequent treatment. DOT, BOR, PFS, safety and all baseline characteristics for each of the following subgroups will be described as exploratory endpoints: sequencing post-cabozantinib, long-responders, non-responders, cabozantinib &amp; rechallenge, cabozantinib &amp; therapeutic schedules, cabozantinib &amp; local treatment, cabozantinib &amp; elderly patients. Data will be analyzed descriptively. Due to the observational nature of this study, no formal calculation of sample size and statistical power were performed. With a sample size of 300 participants who started cabozantinib in 2 nd line between 1 st March 2018 and 1 st March 2021 and a median DOT of 7.6 months, the two-sided confidence interval of the median will be estimated with a width equal to 1.7 months (95% Confidence Interval [CI] [6.8; 8.6]) and a censoring probability near 0. All collected data will be in accordance with the daily practice of medical doctors, with a maximum follow-up of 12-months. Data collection started in Q3 2022 and the first patient was included on September 16 th 2022. No interim analysis is planned. This study is funded by Ipsen Pharma. Clinical trial information: NCT05444933 .
Nivoswitch trial: Predictive value of PD-L1 in plasma and extracellular vesicles.
Authors: JAdzia Sonnleithner, Dirk Himbert, Philip Zeuschner, Arndt Hartmann, Carsten Grüllich, Philipp Ivanyi, Manfred Wirth, Peter Staib, Martin Schostak, Philip Dargatz, Lothar Müller, Viktor Grünwald, Kerstin Junker
Journal: Journal of Clinical Oncology (2023)

718 Background: Predictive markers for immune checkpoint inhibition (ICI) in renal cell carcinoma patients are still missing. Until now, mainly primary tumor tissues have been analyzed to identify reliable markers including PD-L1, although distant metastases represent the therapy targets. Taking into account putative heterogeneity between primary tumors and metastases as well as dynamic changes during tumor progression and treatment, markers from liquid biopsies seem to be more suitable. The aim of this study was to investigate the predictive value of PD-L1 in plasma and on extracellular vesicles (EV) from plasma in the Nivoswitch trial. Methods: Plasma samples at randomization were obtained from 39 patients who received 3 months of tyrosine kinase inhibitor (TKI) therapy followed by random allocation to Nivolumab (“switch arm”) or continued TKI therapy (control arm) and during treatment (day 30). PD-L1 concentration was quantified by ELISA. EVs were isolated by ultracentrifugation or by using a commercial kit. They were characterized by Western blotting using cell specific, EV-specific markers as well as PD-L1 antibody. The data was analyzed by Mann Whitney and Kruskal Wallis tests as well as Kaplan Meier estimates. Results: PD-L1 was detected in plasma and EVs in all patients. PD-L1 plasma concentration was similar between response categories both in the overall cohort and the control (TKI) arm. In contrast, PD-L1 concentration in the “switch arm” was significantly lower in patients with objective response compared to patients with stable (p=0.028) or progressive disease (p=0.008) at day 0, whereas no significant difference occurred at day 30. Plasma PD-L1 levels during treatment (day 30 compared to day 0) did not show an association with therapy response in both arms. A trend towards better OS was found in patients with lower PD-L1 irrespective of treatment arm, but not for PFS. PD-L1 was detected on plasma EVs both by Western blotting as well as by ELISA, although the concentrations were too low for statistical analysis. Conclusions: In this study, plasma PD-L1 concentration did not show strong associations with clinical outcomes which might be caused by the rather small sample size and inherent heterogeneity of treatment. However, PD-L1 concentrations may have prognostic value confirming published data on tumor tissues. PD-L1 is detectable on EVs from plasma. Further studies should investigate the potential of EVs as biomarkers as well as their functional role in therapy response, especially in ICI. Clinical trial information: NCT02959554 .